Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder

Elia, J., Glessner, J. T., Wang, K., Takahashi, N., Shtir, C. J., Hadley, D., Sleiman, P. M. A., Zhang, H., Kim, C. E., Robison, R., Lyon, G. J., Flory, J. H., Bradfield, J. P., Imielinski, M., Hou, C., Frackelton, E. C., Chiavacci, R. M., Sakurai, T., Rabin, C., Middleton, F. A., Thomas, K. A., Garris, M., Mentch, F., Freitag, C. M., Steinhausen, H. C., Todorov, A. A., Reif, A., Rothenberger, A., Franke, B., Mick, E. O., Roeyers, H., Buitelaar, J., Lesch, K. P., Banaschewski, T., Ebstein, R. P., Mulas, F., Oades, R. D., Sergeant, J., Sonuga-Barke, E., Renner, T. J., Romanos, M., Romanos, J., Warnke, A., Walitza, S., Meyer, J., Pálmason, H., Seitz, C., Loo, S. K., Smalley, S. L., Biederman, J., Kent, L., Asherson, P., Anney, R. J. L., Gaynor, J. W., Shaw, P., Devoto, M., White, P. S., Grant, S. F. A., Buxbaum, J. D., Rapoport, J. L., Williams, N. M., Nelson, S. F., Faraone, S. V., Hakonarson, H. (2012) Genome-wide copy number variation study associates metabotropic glutamate receptor gene networks with attention deficit hyperactivity disorder. Nature Genetics, 44 (1). pp. 78-84. ISSN 1061-4036

URL: http://www.ncbi.nlm.nih.gov/pubmed/22138692
DOI: 10.1038/ng.1013

Abstract

Attention deficit hyperactivity disorder (ADHD) is a common, heritable neuropsychiatric disorder of unknown etiology. We performed a whole-genome copy number variation (CNV) study on 1,013 cases with ADHD and 4,105 healthy children of European ancestry using 550,000 SNPs. We evaluated statistically significant findings in multiple independent cohorts, with a total of 2,493 cases with ADHD and 9,222 controls of European ancestry, using matched platforms. CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10 -9). We saw GRM5 (encoding glutamate receptor, metabotropic 5) deletions in ten cases and one control (P = 1.36 × 10 -6). We saw GRM7 deletions in six cases, and we saw GRM8 deletions in eight cases and no controls. GRM1 was duplicated in eight cases. We experimentally validated the observed variants using quantitative RT-PCR. A gene network analysis showed that genes interacting with the genes in the GRM family are enriched for CNVs in ∼10% of the cases (P = 4.38 × 10 -10) after correction for occurrence in the controls. We identified rare recurrent CNVs affecting glutamatergic neurotransmission genes that were overrepresented in multiple ADHD cohorts.

Item Type: Paper
Uncontrolled Keywords: metabotropic receptor metabotropic receptor 1 metabotropic receptor 5 metabotropic receptor 7 metabotropic receptor 8 adolescent adult article attention deficit disorder child cohort analysis controlled study copy number variation female gene deletion gene duplication gene interaction gene locus genome analysis genotype human major clinical study male neurotransmission priority journal reverse transcription polymerase chain reaction single nucleotide polymorphism Attention Deficit Disorder with Hyperactivity Child, Preschool DNA Copy Number Variations Gene Regulatory Networks Genetic Predisposition to Disease Humans Polymorphism, Single Nucleotide Receptors, Metabotropic Glutamate
Subjects: bioinformatics > genomics and proteomics
diseases & disorders > mental disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > glutamate receptor
CSHL Authors:
Communities: CSHL labs > Lyon lab
Depositing User: Matt Covey
Date Deposited: 10 Dec 2012 20:13
Last Modified: 01 Feb 2017 17:52
PMCID: PMC4310555
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26304

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